The field of the invention is enhancement of natural immune response, specifically the localization of aggregates of lymphocytes in desired regions of the body by application of electrical stimulation.
Stimulation of the body's own immune defenses to ward off infection or to attack tumors is preferable in many cases to chemical or surgical intervention, or can be useful to augment such therapies. For example, chemotherapeutic agents often act to inhibit cell division, in order to slow tumor growth sufficiently to allow the normal immune response to eliminate tumor cells. Such chemotherapeutic agents are not specific for tumor cells and also inhibit normal cell division, leading to prodigious toxic side effects. In other cases, tumors, particularly of the brain, are inaccessible surgically or can be only partially resected. Moreover, tumors in the brain tend to be sealed off from the immune system by the blood-brain barrier which sharply curtails access of circulating immune cells to the brain. A method of stimulating an immune response against cells which have undergone neoplastic transformation, for example, would augment the effectiveness of various chemical and surgical interventions, reducing side effects and improving outcome.
Effector lymphocytes responsible for cellular immune responses can be classified into three major classes, namely NK (natural killer) cells, a minority population, and helper/inducer (T4) and suppressor/cytotoxic (T8) cells, which together make up the majority of lymphocytes in the circulating blood. T lymphocytes and natural killer cells effect cell mediated immunity. B lymphocytes differentiate into plasma cells that produce antibodies specific for the stimulating antigen. Antibody production is referred to as humoral immunity. Upon activation, T cells proliferate and are released into the circulation and thence ultimately reach tissues. Generally, lymphocytes are activated only in response to a specific antigen, but artificial means of activating them have been found, for example, lectins such as Concanavalin A and electrical stimulation (Bourguignon et al., J. Cellular Biochem. 37:131-150, 1988).
Natural killer cells can directly attack tumor cells and cells that have been invaded by viruses. Cytotoxic T cells also attack tumor cells and virus-infected cells by binding to the antigen-bearing target cell. To bind and activate the T cell however, the foreign antigen must first be processed and presented to the cytotoxic T cell in the context of the appropriate histocompatibility complex molecule (MHC). Other adhesion molecules on the membranes of the T cells and their target cells also assist in the binding and activation of the T cells. Ultimately the activated T cell, like the NK cell, kills the target cell by constructing pores in the target cell membrane and inducing death by apoptosis. Helper T cells act to increase the activation of macrophages, B cells and other T cells by secreting lymphokines (interleukin-2, gamma-interferon, etc.). This enhances the efficacy of the lymphocyte response in tumored or infected tissue. Suppressor T cells modulate the response of other T cells to prevent excessive or auto-immune reactions.
The use of electrical stimulation to promote bone and soft tissue healing is known (see e.g., J. Black, Clin. Plast. Surg Apr. 12, 1885 (2):243-57).
The therapeutic value of stimulated lymphocytes to treat brain tumors is known; for example U.S. Pat. No. 4,902,288 (incorporated by reference) describes immunotherapy for tumors using implantable, stimulated lymphocytes. Use of the instant invention to enhance the number and improve the distribution of lymphocytes to all areas of a tumor, including the invading edge, such as in the brain following surgical debulking of a tumor or in an inoperable tumor, could substantially improve or replace traditional therapies, and lead to enhanced patient survival and quality of life.